Heparins are polysaccharides widely distributed in animal tissues. As a result of an incomplete biosynthesis, heparins have hybrid structures which can be statistically represented by "average" disaccharide repeating units intermediate between the non-sulfated units of the precursor (A) ##STR1## and the trisulfate units (B) ##STR2##
It is understood that heparin is not a single molecule represented by an intermediate structure between the (A) and the (B) ones having n disaccharide units. It is a population of molecules all having an intermediate structure between the (A) and the (B) ones having a very variable value of n as specified hereinbelow.
Practically, heparin is a polysaccharide composed of molecules of glucuronic acid and iduronic acid largely sulfated in 2-position, linked to molecules of glucosamine largely sulfated in 6-position and sulfated or acetylated on the amine in 2-position.
The structure of heparin may be statistically represented by the following formula ##STR3## wherein A represents H and SO.sub.3.sup.-, B represents SO.sub.3.sup.- and COCH.sub.3 and n is an integer from 20 to 30.
The expression "n is an integer from 20 to 30" means that most of the heparin molecules is represented by the structure I above, where the disaccharide unit is repeated from 20 to 30 times, which corresponds to a molecular weight of from 12000 to 18000.
The expressions "H and SO.sub.3.sup.- " and "SD.sub.3.sup.- and "COCH.sub.3 ", as used herein for the substituents A and B, respectively, indicate that in the above 20 to 30 disaccharide units A is in some cases hydrogen and in other cases a SO.sub.3.sup.- group and, analogously, B in most of cases is SO.sub.3.sup.- and in other cases is an acetyl group.
Likewise, the bond , as herein drawn, indicates that the COO.sup.- group, in some of the 20 to 30 disaccharide units has the configuration ##STR4## of the D-glucuronic acid and in most of said n units has the configuration ##STR5## of the L-iduronic acid.
Heparin possesses a good antithrombotic activity and, therefore, it is used particularly in the prevention of postoperative deep venous thrombosis. However, the antithrombotic activity of heparin is broadly ascribed to its anticoagulant action and, therefore, it causes the physician serious problems of monitoring because of the high risk for hemorrhage associated with heparin therapy.
The structure and the properties of heparins are summarized in a paper by B. Casu et al. (Arzneimittel-Forschung 1983, 33, 135-142) which shows that the hydroxy groups in the position 3 of the glucosamine and of the iduronic or glucuronic acids subunits are not sulfated, even though minor amounts of 3-O-sulfate groups, not exceeding 1% (U. Lindhal et al., Proc. Natl. Acad. Sci. USA 1980, 77, 6551-6555; B. Casu et al., Biochem. J. 1981, 197, 599-609), have been detected. The above Casu et al. paper describes a series of natural heparins having a very large spectrum of sulfation degree which, in the case of a highly purified beef lung heparin, reaches 2.55, namely the highest sulfation degree never found in a heparin, showing that such a heparin is rich in structures (B) above.
Polysaccharides other than heparin have been sulfated and transformed into the so-called "heparinoids" which are active on the coagulation system. The polyxylan sulfate, also named SP-54, having the structure ##STR6## where R is SO.sub.3 NA or H, is used as a therapeutically active agent, but it is chemically different from heparin. More particularly, polyxylan sulfate has not any primary hydroxy group nor any N-sulfate group.